Pain is a major component of inflammation, but the role of pain-sensing nociceptor neurons in the regulating the inflammatory process is not well understood. It is increasingly clear that molecular and cellular interactions between the nervous system and immune system play important roles in development, homeostasis, and tissue inflammation. Nociceptor neurons are specialized to detect noxious/harmful stimuli and upon activation, transduce the sensation of pain. Nociceptor neurons densely innervate peripheral tissues including the skin, lungs, and gastrointestinal tract, tissues that are often exposed to pathogenic infection. Bacterial infection often produces significant pain. Our previous work demonstrated that S. aureus directly activates nociceptor neurons through release of N-formyl peptides and the pore-forming toxin ?emolysin, thereby producing pain. Upon activation, these nociceptor neurons release neuropeptides that are able to directly act on the immune system. Thus, like the immune system, the nervous system is able to directly detect and respond to pathogens. We hypothesize that nociceptor neurons may play an important and previously unappreciated role in host defense against pathogens. The goal of this study is to determine the contribution of nociceptor neurons and their neuropeptides in modulating the function of both innate and adaptive immune cells during bacterial host defense. We will utilize specific genetic and pharmacological tools to silence or activate nociceptor neuron activity with microbiological and immunological analyses to ascertain the significance of neuro-immune communication in host defense against S. aureus infection. These experiments will test the role of nociceptor neurons in the regulation of: 1) Neutrophil and monocyte mediated clearance of S. aureus and dendritic cell activation during infection. 2) T cell responses to S. aureus including priming in lymph nodes and effector function at the site of infection. These analyses will determine the role of nociceptor neurons in regulating immunity and inflammation, a relatively unexplored and potentially significant area of research. These studies have the potential to transform our understanding of host-pathogen interactions and of neuro-immune mechanisms in bacterial host defense.